Abstract

The insertion of the higher homologues of the \alpha-amino acids, specifically \beta, \gamma, and \delta residues, into a peptide sequences results in hybrid structures with novel hydrogen-bonding possibilities.[1] Research in this area of hybrid polypeptides has been stimulated by the observation of novel helical structures in \beta oligopeptides in which the hydrogen-bond polarities are reversed. For example, the 12 helix $(2.5_{12}$ or $2.5_1-P)$ in a $(\beta)_n$ sequence maintains the same directionality $(C=O(i)^{...}NH(i+3))$ as the canonical $3_{10}$ helixin an $(\alpha)_n$ sequence[2] and may be formally considered as an expanded version of the latter. By contrast, the 14 helix $(3_{14}$ or $3_1-M)$ in a $(\beta)_n$ sequence possesses a reversed hydrogen-bond polarity $(NH(i)^{...}C=O(i+2))$.[3] Initial crystallographic results with hybrid \alpha\beta and \alpha\gamma sequences suggest that the expanded analogues of the $3_{10}$ helix, namely, the $C_{11}$ $(\alpha\beta)$ and $C_{12}$ $(\alpha\gamma)$ helices, can indeed be observed in short peptides.[4] Calculations suggest that helices with alternating hydrogen-bond polarities may indeed be stable structures in hybrid sequences.[1c,d] In this Communication, we report the $C_{12}/C_{10}$ mixed hydrogen-bonding pattern in the crystal structure of the tetrapeptide Boc-Leu-Gpn-Leu-Aib-OMe (1; Boc: tertbutoxycarbonyl; Gpn: 1-(aminomethyl)cyclohexaneacetic acid (gabapentin); Aib: aminoisobutyric acid), which was serendipitously obtained during the synthesis of longer hybrid sequences. This novel helical conformation can be generalized as an $(\alpha\gamma)_n$ sequence. The sequence contains the stereochemically constrained \gamma residue gabapentin, which is an achiral \beta,\beta-disubstituted \gamma-amino acid. The presence of gem-dialkyl substituents on the $C\beta$ atom limits the torsion angles about the $C{\gamma}-C{\beta}$ $(\theta_1)$ and $C{\beta}-C{\alpha}$ $(\theta_2)$ bonds to approximately $\pm 60^o$.[5]